Thrombosis, or blood clotting, can be the pathophysiological basis for a number of undesirable vascular complications. However, the ability to manage a patient's propensity to clot or bleed is currently limited. Efforts have been made toward the development of drugs that modify an individual's thrombotic state. Administration of antithrombotic therapy helps restore blood flow following vascular occlusion. Pro-hemostatic therapy, on the other hand, helps control provoked or spontaneous bleeding. However, some antithrombotic therapies can precipitate bleeding and some hemostatic therapies can result in excessive clotting.
Moreover, the methods used to treat thrombotic conditions have become increasingly complex as newer therapies are developed and combined into disease-specific therapies, increasing the difficulties of assessing patients' conditions. For example, when treating a patient with myocardial infarction, as many as five or six agents targeting different molecular pathways of thrombosis are typically administered, such as aspirin, clopidogrel, and integrillin, which are anti-platelet drugs, and heparin, lovenox, and bivalirtudin, which are anti-coagulant drugs. Chronically, patients may be treated with aspirin, plavix, and/or warfarin, or other oral coagulation inhibitors. The dosing, the timing of administration, and the manner in which novel therapies are to be incorporated (e.g., administering higher doses of clopidogrel or switching to Prasugrel, either of which can increase bleeding risk if applied too broadly) is a matter of debate. In fact, an increasing number of patients are being recruited into expensive clinical trials in an attempt to resolve these questions of proper therapies before the solutions are outdated. Notwithstanding, over 12 million people die each year from heart attacks, which remains the leading, and a still growing, cause of death worldwide.
A similar set of concerns are present in a number of other highly prevalent diseases, such as ischemic stroke, pulmonary embolism, deep vein thrombosis, atrial fibrillation, and dilated heart failure, as well as iatrogenically induced conditions, such as those that follow endovascular device therapy (e.g., placing stents, artificial valves, ventricular assist devices). The treatment of these cardiovascular diseases is made more complex when a patient simultaneously has a known bleeding condition, such as intracranial or gastrointestinal bleed. Clinicians, however, are continually faced with choosing an appropriate management strategy for such cases on a daily basis. Achieving an optimal balance between clotting and bleeding risk is cornerstone in the treatment of many vascular diseases and in the optimization of surgical risk. Notwithstanding these continued efforts, many therapies chosen can be sufficient for some individuals, but sub-therapeutic or supra-therapeutic for others. In other words, clot formation and bleeding risk is highly individual and influenced by a host of environmental and genetic factors which modulate an integrated risk.
The individualized character of thrombotic/bleed risk has led to extensive efforts to understand individual risk and, thus, personalize medical therapy. A variety of assays attempt to gauge a patient's propensity to clot or bleed, yet none offer an accurate, universal method of clinical risk assessment. Genetic testing is limited by the enormous impact environment has on thromboses. In addition, co-existing illnesses, medical therapies, and even trauma itself, greatly affect an individual's propensity to clot. Functional tests that directly measure the clotting process offer a way to integrate genetic and environmental influences. However, current clinical techniques only consider isolated aspects of the complex thrombotic process under contrived exposure conditions. Moreover, while large clinical trials target populations, performing analysis on smaller populations or subsets allows certain risk factors to be identified more specifically. Clinical risk scores have been developed that classify risk based on the number of independent risk predictors a patient may have. However, this methodology works for small populations or subpopulations better than at the individual patient level.
Accordingly, while forming clinical risk scores and/or collecting genetic data allows arriving at a more refined assessment of risk, these approaches can be limited. As one example, by following only the initial risk assessment and selection of therapy, these methods do not allow continued monitoring of any altered risk, such as may occur based on the chosen therapy. In other words, the above-described strategies are essentially “open loop,” and are not designed to monitor and/or adjust to changing conditions after the initial therapeutic recommendation is chosen.
A variety of presently practiced functional assays attempt to assess not only a patient's baseline state, but also the patient's changing state in response to therapy, offering the potential for “closed-loop” control. Examples of such techniques include standard blood assays, such as whole blood or light transmission platelet aggregation studies. More complex assays can incorporate blood inducers of aggregation in addition to a reactive surface onto coated surfaces (e.g., fibrinogen-coated beads) to assess platelet function. Still other assays can expose blood to reagents, a surface, and blood flow conditions simultaneously to detect clot formation. Each of the aforementioned tools attempt to find a better predictive assay for an individual's thrombotic risk and response to therapy, and have been applied towards the evaluation of drug resistance patterns.
One observation resulting from these studies is the tremendous variability in the predictions. For instance, the prevalence of aspirin resistance varies between 4% and 60% depending on the assay used. Similarly, clopidogrel resistance can vary between 5% and 30%. Moreover, while these assays may target a specific drug, they do not account for the complex multi-drug environments that are used in real-world clinical practice, nor do they account for the constant flux in practice as new drugs are developed and others phased out. Moreover, these assay tests only consider an isolated aspect of thrombosis, such as platelet response. In reality, however, blood clots result from a complex interplay between platelet activation, aggregation, and adhesion, along with coagulation activation, all of which function in a powerful feed-forward loop. While other testing techniques, such as determining prothrombin time or activated partial thromboplastin time, may detect aspects of coagulation function, these techniques also fail to consider the important, interactive mechanisms that cause clinical blood clotting. Therefore, these isolated assays of specific aspects of clot formation fall short in their effectiveness and clinical utility. Presently, there is no standardized approach to assaying individual drug resistance patterns, nor for determining individual thrombotic risk as a whole.
Accordingly, there exists a need for improved techniques for performing thrombotic assays, and more particularly, for performing multi-parameter thrombotic assays to generate a thrombotic profile and characterizing patients' thrombotic state and/or risks associated therewith.